The purpose of this research program is to deepen our understanding of how drugs and dyes bind to DNA and exert their pharamaclogical action. This is being accomplished by X-ray crystallographic studies of drug-nucleic acid crystalline complexes in our laboratory. We have determined the three-dimensional structures of fifteen different drug-dinucleoside monophosphate crystalline complexes by X-ray crystallography. From this work -- and work by others -- we are able to distinguish two classes of intercalating compounds -- simple intercalators and complex intercalators. Simple intercalators bind to the "kink" in both DNA and double-stranded RNA (i.e., the C3' endo (3'-5') C2' endo structure). Their interactions are "simple" in the sense that they involve stacking interactions with the base-pairs and electrostatic interactions with the sugar-phosphate chains. Simple intercalators have a sequence binding perference -- CPG and TPA -- and bind to DNA in a neighbor exclusion mode at high drug/DNA binding ratios. Characteristically, simple intercalators unwind DNA about -26. Examples are: ethidium, acridine orange, 9-aminoacridine, ellipticine, terpyridine platinum tetramethyl-N-methylphenanthrolinium and N,N-dimethylproflavine. Complex intercalators utilize additional types of interactions when binding to DNA or RNA. These may be hydrogen bonding interactions with the bases (actinomycin, daunomycin) or with the sugar-phosphate chains (proflaving).